Tail-anchored (TA) proteins, including the Bcl-2 family members, characteristically tether to phospholipid bilayers by a single hydrophobic segment at the carboxy (C)-terminus with the bulk of the molecule located in the cytosol. Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. The biological function of Bcl-2 related proteins is inextricably linked to their specific subcellular localization; the cytosol, endoplasmic reticitulum (ER) membranes or mitochondria outer membrane (MOM). The Bcl-2 family members have been shown to govern mitochondrial outer membrane permeabilization (MOMP) and can be either pro-apoptotic (e.g., Bax, BAD, Bak, Bok, Bcl-Xs, Bik, Bim, Bid, Egl-1, and Diva among others) or anti-apoptotic (e.g., Bcl-2 proper, Bcl-xL, Mcl-1, CED-9, A1, Bcl-w, and Bfl-1 among others).
Bcl-2 family members have been implicated in a number of disorders, including cancer, for example, melanoma, breast, prostate, and lung; as well as neurological disorders, for example, schizophrenia; and immunological disorders. Cancers and hyperplasias include a variety of very complicated diseases; nevertheless, they all share a common feature that all the cells are hyperproliferative and are able to continue dividing, and do not undergo terminal differentiation. This supports a role for reduced apoptosis in the etiology of these and other related disorders.
While several current cancer therapies promote cancer cell death and inhibit cancer cell growth, many of these therapies are highly toxic to cancer patients and their administration results in a multitude of unpleasant and unbearable side effects. In addition, many of the presently available cancer therapeutics deomonstrate efficacy only against cancers or hyperplasias of specific etiology. Therefore, a treatment that promotes cancer cell death across a broad class of cancer cell types and origins, and is largely non-toxic to patients is highly desirable.
Recently, we demonstrated that anti-apoptotic Bfl-1 contains a unique amphipathic tail-anchoring peptide (ATAP) at amino acids 147-175. As described herein, the Bfl-1 ATAP contains charged amino acids lining to one side of the alpha-helix. Within the human genome, a homologous ATAP sequence is present in another tumor suppressor gene, the human cervical cancer suppressor-1 (HCCS-1). An additional mitochondria-targeting signal (MTS) at the N terminus of HCCS1 contributes to its mitochondria targeting and apoptotic function.
Our experimental results indicate that ATAP peptides are capable of modulating the apoptotic cascade. As such, ATAP peptides can be adapted into a highly effective therapeutic agents to treat a number of diseases, including bacterial infections, cancers and hyperplasias.